A number of small peptide like compounds which inhibit metalloproteinase have been described. Perhaps the most notable of these are those relating to the angiotensin converting enzyme (ACE) where such agents act to blockade the conversion of the decapeptide angiotensin I to angiotensin II, a potent pressor substance. Compounds of this type are described in EP-A-0012401.
Certain hydroxamic acids have been suggested as collagenase inhibitor as in U.S. Pat. No. 4,599,361; WO-A-9005716 and WO-A-9005719. Other hydroxamic acids have been prepared as ACE inhibitors, for example, in U.S. Pat. No. 4,105,789, while still others have been described as enkephalinase inhibitors as in U.S. Pat. No. 4,495,540.
The hydroxamic and carboxylic acids of the current invention act as inhibitors of mammalian matrix metalloproteinases (MMPs). The MMPs include, for example, collagenase, stromelysin and gelatinase. Since the MMPs are involved in the breakdown of the extracellular matrix of articular cartilage (Arthritis and Rheumatism, 20, 1231-1239, (1977)), potent inhibitors of the MMPs may be useful in the treatment of arthritides, for example, osteoarthritis and rheumatoid arthritis and other diseases which involve the breakdown of extracellular matrix. These diseases include corneal ulceration, osteoporosis, periodontitis, tumor growth and metastasis.
The use of hydroxamic acid derivatives for the effective inhibition of the destruction of articular cartilage as a model of rheumatoid and osteoarthritis has been demonstrated (Int. J. Tiss. Reac., XIII, 237-243 (1991)).
Topical application of hydroxamate inhibitors may be effective against corneal ulceration as demonstrated in the alkali-injured cornea model (Invest. Ophthalmol Vis. Sci., 33, 33256-3331 (1991)).
In periodontitis, the effecticeness of tetracycline has been attributed to its collagenase inhibitory activaty (J. Perio. Res., 28, 379-385 (1993)).
Hydroxamic acid derivatives have also been effective in models of tumor growth (Cancer Research, 53, 2087-2091 (1993)) and tumor invasion (Mol. Cell Biol., 9, 2133-2141 (1989)).
The current invention relates to a series of hydroxamic and carboxylic acids, which act as inhibitors of matrix metalloproteinases, their preparation, pharmaceutical compositions containing them, and the intermediates involved in their preparation.